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VPS53 gene is associated with a new phenotype of complicated hereditary spastic paraparesis

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Abstract

Hereditary spastic paraparesis (HSP) is a progressive neurodegenerative disorder, characterized by progressive lower limb weakness and spasticity. Multiple genes are associated with both the pure and complicated HSP types. Our study is aimed at seeking for novel genetic basis of HSP in a family with two affected siblings. Genetic analysis using whole exome sequencing was conducted in a family quartet with two female siblings, who presented with complicated HSP featuring slowly progressive paraparesis, mild-moderate intellectual disability, normal head circumference (HC), and normal magnetic resonance imaging (MRI). A homozygous pathogenic variant was identified in both siblings in the VPS53 gene (c.2084A>G: c.2084A>G, p.Gln695Arg). This gene acts as a component of the Golgi-associated retrograde protein (GARP) complex that is involved, among others, in intracellular cholesterol transport and sphingolipid homeostasis in lysosomes and was previously associated with progressive cerebello-cerebral atrophy (PCCA) type 2. This is the first description of the VPS53 gene as a cause of autosomal recessive complicated HSP. Lysosomal dysfunction as a result of impaired cholesterol trafficking can explain the neurodegenerative processes responsible for the HSP. Our finding expands the phenotype of VPS53-related disease and warrants the addition of VPS53 analysis to the genetic investigation in patients with autosomal recessive HSP. The exact role of GARP complex in neurodegenerative processes should be further elucidated.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

HSP:

Hereditary spastic paraparesis

PCCA:

Progressive cerebello-cerebral atrophy

GARP:

Golgi-associated retrograde protein

HC:

Head circumference

MRI:

Magnetic resonance imaging

MRS:

Magnetic resonance spectroscopy

ID:

Intellectual disability

ADHD:

Attention deficit hyperactivity disorder

CMA:

Chromosomal microarray analysis

WES:

Whole exome sequencing

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Acknowledgments

Irina Opincariu is thanked for editorial assistance. We would like to express our sincere gratitude to the patients and their family.

Funding

The study received the Bircher-Benner Grant for Preventative Medicine from the Sackler Faculty of Medicine, Tel Aviv University.

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Authors and Affiliations

  1. Pediatric Neurology Institute, Dana-Dwek Children’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Moran Hausman-Kedem, Shay Menascu, Karen Geva, Liora Sagie & Aviva Fattal-Valevski

  2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Moran Hausman-Kedem, Shay Ben-Shachar, Shay Menascu, Karen Geva, Liora Sagie & Aviva Fattal-Valevski

  3. Genetic Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Shay Ben-Shachar

  4. Multiple Sclerosis Center, Sheba Medical Center, Tel HaShomer, Israel

    Shay Menascu

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  1. Moran Hausman-Kedem
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Correspondence to Moran Hausman-Kedem.

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All study protocols were reviewed and approved by the Institutional Review Board at the Tel Aviv Sourasky Medical Center.

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Hausman-Kedem, M., Ben-Shachar, S., Menascu, S. et al. VPS53 gene is associated with a new phenotype of complicated hereditary spastic paraparesis. Neurogenetics 20, 187–195 (2019). https://doi.org/10.1007/s10048-019-00586-1

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  • DOI: https://doi.org/10.1007/s10048-019-00586-1

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